Introduction on Vestibular Disorders
Vestibular (inner ear) disorders can cause dizziness, vertigo, imbalance, hearing changes, nausea, fatigue, anxiety, difficulty concentrating, and other symptoms, with potentially devastating effects on a person's day-to-day functioning, ability to work, relationships with family and friends, and quality of life.
For example, vestibular neuritis is the first cause of hospitalisation for non neurological vertigos. Because its aetiology is largely unknown, epidemiological studies are variable depending on the source (its incidence is believed to be between 3.5 and 50 new cases for 100000 persons/per year). In the past, either an inflammation of the vestibular nerve or labyrinthine ischemia was proposed as a cause of vestibular neuritis. Currently, a viral cause is favoured. A reactivation of herpes simplex virus type 1 would explain the repetition of the vertigo crisis under such a situation.
Vestibular disorders may be also involved in the majority of the fall in the elderly and their prevention became a priority. The fall in the elderly represents indeed more than 1% of the total budget of the health insurance in France (INSEE 1990). It affects in France 30% of people above 65 and 50% above 80. The fall in the elderly is involved in ⅔ of the death caused by accident above 65, and multiplies by 4 the risk of death in the following year.
Aetiology of Vestibular Disorders
Although the aetiology of vestibular disorders is mostly unknown, it is widely accepted that vestibular disorders (also called vestibular deficits) constitute a vast family of conditions wherein the vestibule organ is associated. These disorders may be distinguished by their putative origins, one can thus identify (1) lesional vestibular disorders and (2) non lesional vestibular disorders.    1) Lesional vestibular disorders refer to vestibular disorders wherein lesions on inner ear cells and/or vestibular nerve are present or will appear during the disorder time course. In this case, the functionality of the vestibule is impaired as it can be observed using clinical functional tests (VOR, VNG). Lesional vestibular disorders include:            vestibular disorders wherein an infection inflames the inner ear and/or the vestibular nerve inducing reversible and/or irreversible damages. One example of conditions from this group is vestibular neuritis.        vestibular disorders wherein inner ear fluid levels are affected (abnormalities in the quantity, composition, and/or pressure of the endolymph), these disorders usually develop lesions during the disease time course. Examples of conditions from this group are Ménière's disease and secondary endolymphatic hydrops. They are currently associated with tinnitus and hearing loss.        Vestibular disorders induced by insults or lesions of the vestibular endorgans. Examples of said conditions are vertigo caused by local ischemia, excitotoxicity, trauma that affect temporal bones.            2) Non-lesional vestibular disorders refer to vestibular disorders supported by transient and often iterative vertigo crisis wherein no lesion on inner ear cells and/or vestibular nerve can be observed. In this case, the functionality of the vestibule evaluated between the vertigo crisis using functional tests (VOR, VNG) do not differ from healthy vestibule. Non-lesional vestibular disorders include:            vestibular disorders wherein debris had been collected within a part of the inner ear. This debris, called otoconia, is made up of small crystals of calcium carbonate and when they shift, they send false signals to the brain. Examples of said conditions are positional vertigos.        Iterative vestibular disorders of unknown origin without tinnitus or hearing loss.        
Evaluation of the Vestibule Functional Loss
In human, morphofunctional alterations of the vestibular endorgans cannot be evaluated directly (excepted for large lesions that can be detected by IRM). Rather indirect assessment methods are currently used to evaluate the loss of functionality of the vestibule. These behaviour testing methods are generally conducted at ENT clinic/hospitals. Among them we can cite the vestibulonystagmography (VNG), assessment of the vestibuloocculomotor reflex (VOR) using caloric or rotational tests.
Treatments of Vestibular Deficits
Current treatments of vestibular deficits mainly focus on reducing the vertigo crisis using vestibuloplegic drugs, while limiting neurovegetative reactions by using anti emetic drugs. Corticosteroids and antiviral drugs are the only medication that tries to limit the spread of vestibular damages in the case of vestibular neuritis (that are assumed to be due to bacterial or virus infections). Their effect remains under debate regarding the lack of aetiology in most vestibular deficits. For example, recovery after vestibular neuritis is usually incomplete. In a study of 60 patients, horizontal semicircular canal paresis was found in about 90% one month after the onset of symptoms, and in 80% after six months; the caloric responses normalized in only 42%. On the basis of the incidence of this condition, a substantial and permanent unilateral dynamic deficit of the vestibulo ocular reflex, which cannot be compensated for by other mechanisms, develops in approximately 4000 person per year in the United States. This deficit leads to impaired vision and postural imbalance during walking and especially during head movement toward the affected ear.
Accordingly, there is a need for a protective or repair therapy that prevent, reduce or treat the incidence and/or severity of lesional vestibular disorders, said functional alteration of the inner ear cells and/or vestibular nerve being due to an inflammation, lesions or insults of diverse origins.
The inventors surprisingly found that serotonin 5-HT3 receptors antagonists such as ondansetron were able to prevent or treat vestibular lesions by protecting inner ear cells and vestibular nerve from damage or degeneration. Ondansetron is known from Jellish et al. (Journal of Clinical Anesthesia 2007, 9:451-456) for reduction of postoperative nausea or vomiting after chirurgical treatment of the middle ear. Ondansetron is also known from Rice et al. (The Lancet 1995, 345:1182-1183) for treating symptoms such as vertigo, nausea and vomiting in brainstem disorders such as multiple sclerosis. Finally, ondansetron is also known from US2007265329 for preventing nausea and vomiting induced by chemotherapy. The anti-emetic properties of ondansetron has been reported to be mediated by an antagonization of the 5-HT3 serotonin receptors located in the vomiting centre (brain stem lateral reticular formation) that receives vestibular, somatic, visceral and limbic afferents (Tyers M B, Freeman A J. Oncology, 1992, 49:263-268). This pharmacological action prevents the vomiting reflex usually mediated by serotonin.
While Ondansetron was used for treating or preventing emetic symptoms associated with vertigo, the inventors found that it is also capable of preventing and/or treating direct insults or lesions within vestibular organs.